Evolution of Lutropin to Chorionic Gonadotropin Generates a Specific Routing Signal for Apical Release in Vivo

Jablonka‐Shariff, Albina; Campayo, Javier García; Boime, Irving

doi:10.1074/jbc.c100402200

Cited by 29 publications

(36 citation statements)

References 32 publications

(35 reference statements)

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“…Whereas the secretion of the hLH␤ subunit from transfected MDCK cells was basolateral, the hCG␤ subunit was routed to the apical secretion pathway, primarily because of the O-glycosylated CTP. These results suggested that the O-linked glycans are a major factor for the secretion of hCG into the maternal blood, a crucial step in sustaining high circulating levels in pregnancy (24).…”

mentioning

confidence: 91%

“…Because of this function, a key question is whether the hCG␤boCTP chimera is sorted to the apical secretory pathway, like the hCG␤ subunit, or is released through the basolateral compartment as the human LH␤ subunit and the O-deglycosylated CG␤ subunit (24). We addressed this point, using the MDCK cell model that was validated previously, to study the secretion patterns of the gonadotropins and their subunits (24,25). The hCG␤boCTP chimera was stably transfected into the cell line, and several clones were selected, grown in Transwells, labeled, and analyzed.…”

Section: N-linked Glycan Modification Of the Lh␤ Subunit Derivates-n-mentioning

confidence: 99%

“…Secretion of the hCG␤-boCTP Chimera from Polarized MDCK Cells-It has been reported that hCG release to the maternal compartment is through the apical face of the placenta and is attributed to the O-glycans attached to the CTP of the hCG␤ subunit (24). Because of this function, a key question is whether the hCG␤boCTP chimera is sorted to the apical secretory pathway, like the hCG␤ subunit, or is released through the basolateral compartment as the human LH␤ subunit and the O-deglycosylated CG␤ subunit (24).…”

Section: N-linked Glycan Modification Of the Lh␤ Subunit Derivates-n-mentioning

confidence: 99%

“…Recent studies, utilizing the Madin-Darby canine kidney (MDCK) model, identified sorting determinants in the ␤-subunit of the hormones (24,25). Whereas the secretion of the hLH␤ subunit from transfected MDCK cells was basolateral, the hCG␤ subunit was routed to the apical secretion pathway, primarily because of the O-glycosylated CTP.…”

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confidence: 99%

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The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

Nakav

Jablonka‐Shariff

Kaner

et al. 2005

Journal of Biological Chemistry

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The expression of a previously untranslated carboxylterminal sequence is associated with the ancestral lutropin (LH) ␤ to the ␤-subunit gene evolution of choriogonadotropins (CG). The peptide extension (denoted as CTP) is rich in mucin-type O-glycans and confers new hormonal properties on CG relative to the LH. Although the LH␤ gene is conserved among mammals and only a few frameshift mutations account for the extension, it is merely seen in primates and equids. Bioinformatics identified a CTP-like sequence that is encrypted in the LH␤ gene of several mammalian species but not in birds, amphibians, or fish. We then examined whether or not decoding of the cryptic CTP in the bovine LH␤ gene (boCTP) would be sufficient to generate the LH␤ species of a ruminant with properties typical to the CG␤ subunit. The mutated bovine LH␤-boCTP subunit was expressed and N-glycosylated in transfected Chinese hamster ovary cells. However, unlike human (h) CG␤ CTP, the cryptic boCTP was devoid of mucin O-glycans. This deficiency was further confirmed when the boCTP domain was substituted for the natural CTP in the human CG␤ subunit. Moreover, when expressed in polarized Madin-Darby canine kidney cells, this hCG␤-boCTP chimera was secreted basolaterally rather than from the apical compartment, which is the route of the wild type hCG␤ subunit, a sorting function attributed to the Oglycans attached to the CTP. This result shows that the cryptic peptide does not orientate CG to the apical face of the placenta, to the maternal circulation as seen in primates. The absence of this function, which distinguishes CG from LH, provides an explanation as to why the LH␤ to CG␤ evolution did not occur in ruminants. We propose that in primates and equids, further natural mutations in the progenitor LH␤ gene resulted in the efficient O-glycosylation of the CTP, thus favoring the retention of an elongated reading frame.The family of glycoprotein hormones includes lutropin (LH), 1 follitropin, and thyrotropin, as expressed by the pituitary, and chorionic gonadotropin (CG), which is produced by the placenta of primates and equids (1). Each hormone is a noncovalent heterodimer composed of a common ␣-subunit and a unique ␤-subunit that confers receptor specificity. The ␤-subunits have substantial sequence similarities, including conserved location of cysteine residues that suggests an origin from a common ancestral gene (2). The human (h) CG␤ genes have evolved from an ancestral LH␤ gene by frameshift mutations that resulted in a readthrough into a previously untranslated region and the extension of the reading frame (3, 4) (Fig. 1A). As a result, a short carboxyl-terminal sequence of hLH␤ is replaced by a longer carboxyl-terminal peptide (CTP) in hCG␤ (3-6). In the equine (e), both the placental CG␤ and pituitary LH␤ subunits are products of the same gene (eLH/CG␤) and contain a CTP that is presumed to have evolved by a distinct mechanism (7) (for further explanations see "Results"). Except for primates and equids, no other identified animal species b...

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mentioning

confidence: 91%

Section: N-linked Glycan Modification Of the Lh␤ Subunit Derivates-n-mentioning

confidence: 99%

Section: N-linked Glycan Modification Of the Lh␤ Subunit Derivates-n-mentioning

confidence: 99%

mentioning

confidence: 99%

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The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

Nakav

Jablonka‐Shariff

Kaner

et al. 2005

Journal of Biological Chemistry

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“…Although this pattern is evolutionarily conserved, how distinct modes of gonadotropin secretion affect ovarian development and target cell responses remain unclear. Although models in which variations in secretion of gonadotropins have been achieved in vivo (10) and in vitro, including basolateral and apically polarized secretion (11), the in vivo consequences of altered mode of gonadotropin trafficking and release (constitutive vs. regulated) from pituitary are untested. We sought to identify why the two gonadotropins, LH and FSH, expressed in the same pituitary cell have evolved to exit via different routes to regulate ovarian physiology.…”

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confidence: 99%

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

Wang¹,

Larson²,

Jablonka‐Shariff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.protein sorting | regulated secretion | dense core granules | folliculogenesis

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Gonadotropins

Ulloa‐Aguirre¹,

Dias²,

Bousfield³

2017

Endocrinology

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Evolution of Lutropin to Chorionic Gonadotropin Generates a Specific Routing Signal for Apical Release in Vivo

Cited by 29 publications

References 32 publications

The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

Gonadotropins

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